Project Summary/Abstract The goal of this work is to develop a therapeutic drug that will protect individuals with celiac disease (CD) from intestinal and symptomatic distress they suffer due to minute ingestion of gluten protein. CD is an autoimmune disorder affecting the small intestine, afflicting about 1% of the world?s population, for which there is no known cure. Currently the only therapeutic option to avoid gastrointestinal-related symptoms and potentially long-term health consequences is the life-long strict adherence to a gluten-free diet (GFD). However, a majority of patients never fully recover. Furthermore, recent published analyses indicate that CD patients on average continue to inadvertently consume unsafe levels of gluten while attempting to adhere to a GFD (Ref 13). There is a considerable unmet need for a therapeutic solution to be used as an adjunct to a GFD. ImmunogenX is a clinical-stage biopharmaceutical company developing therapeutic and diagnostic so- lutions for celiac disease. Our lead development, latiglutenase, is an orally administered enzyme product with clinical evidence for histologic protection and symptomatic reduction in CD patients. The FDA, in Type C meetings with ImmunogenX, supports the company?s trial strategy, symptom label, and outcome measur- ing instrument. ImmunogenX?s team has extensive experience in clinical development and operations, regu- latory affairs, biostatistics, and marketing strategy. Latiglutenase, a dual-enzyme drug product, has a strong scientific premise to justify further clinical test- ing. Previous clinical trials have yielded encouraging but inconclusive information regarding its impact on improving mucosal health. The indeterminacy is mostly attributable to shortcomings in one of the trial de- signs that became evident upon review of the trial results. Mucosal healing is relatively slow to manifest. Much stronger evidence was observed for symptom relief due to latiglutenase relative to placebo; however, this benefit was almost exclusively found in a subpopulation of CD patients who remained seropositive de- spite adhering to a GFD. We are beginning to better understand the reasons for this selectivity and also gain- ing more understanding of the prevalence of persistent seropositivity while on a GFD. The proposed NIAID trial will focus on multiple symptom relief for this subpopulation of CD patients, which comprises approxi- mately 20% of all CD patients. In this SBIR Fast Track (Phase I+II) U44 proposal, we propose a randomized, double-blind, placebo-con- trolled, dose-ranging crossover study for diagnosed CD patients who remain symptomatic despite adhering to a gluten free diet. Our enrollment target is based on adequate powering of the primary endpoint for symp- tom reduction. We anticipate the need to prescreen 600 patients to enroll 120 seropositive patients into the screening period (about 20 % of CD patients after 1 year on a GFD remain persistently seropositive), ulti- mately achieving 60 completed patients. Subject recruitment will involve four study centers and will span approximately 18 months. We will employ the recently validated Celiac Disease Symptom Diary patient- reported outcome (CDSD? PRO) instrument for CD symptoms. Phase I will provide a refined trial design, outcome measurement development, statistical tools, and final drug product development to justify clinical trial conduct in Phase II. 1